Casein kinase 1 (CK1) is a family of highly related, constitutively active serine/threonine protein kinases (Christenson E, De Maggio A J and Hockstra M F. (1997). Recent Results Cancer Res. 143, 263-274; Gross S D and Anderson R A. (1998). Cell Signal 10, 699-711).
CK1 is ubiquitously expressed in eukaryotes. Mammalian family members comprise at least seven mammalian CK1 isoforms (α, β, γ1, γ2, γ3, δ and ε) and their various splice variants. (Fish K J, Cegielska A, Getman M E, Landes G M and Virshup D M. (1995). J. Biol. Chem. 270, 14875-14883; Graves P R, Haas D W, Hagedorn C H, De Paoli-Roach A A and Roach P J. (1993). J. Biol. Chem. 268, 6394-6401; Rowles J, Slaughter C, Moomaw C, Hsu J and Cobb M H. (1991). Proc. Natl. Acad. Sci. USA 88, 9548-9552; Zhai L, Graves P R, Robinson L C, Italiano M, Culbertson M R, Rowles J, Cobb M H, De Paoli-Roach A A and Roach P J. (1995). J. Biol. Chem. 270, 12717-12724).
These isoforms share a high degree of similarity within their protein kinase domains. For example CK1δ and CK1ε are 98% identical in this region (Fish K J, Cegielska A, Getman M E, Landes G M and Virshup D M. (1995). J. Biol. Chem. 270, 14875-14883; Graves P R, Haas D W, Hagedorn C H, De Paoli-Roach A A and Roach P J. (1993). J. Biol. Chem. 268, 6394-6401), but show considerable variation in the presence, length and primary structure of the C-terminal non-catalytic domain (Christenson E, De Maggio A J and Hockstra M F. (1997). Recent Results Cancer Res. 143, 263-274). These variable C-terminal domains are responsible for substrate specificity of the different isoforms (Cegielska A, Gietzen K F, Rivers A and Virshup D M. (1998). J. Biol. Chem. 273, 1357-1364; Graves P R and Roach P J. (1995). J. Bio. Chem. 270, 21689-21694) and are involved in the regulation of the interaction with other proteins, and/or subcellular structures.
Autophosphorylation, (Cegielska A, Gietzen K F, Rivers A and Virshup D M. (1998). J. Biol. Chem. 273, 1357-1364; and perhaps dimerization in the case of CK1δ Longenecker K L, Roach P J and Hurley T D. (1998). Acta Crystallogr. D. Biol. Crystallogr. 54, 473-475) are additional mechanisms that regulate CK1 activity, specificity, and sub-cellular localization. The list of known substrates of the CK1 family is still increasing, and so far includes cytoskeleton proteins such as spectrin, troponin, myosin and tau (Simkowski K W and Tao M. (1980) J. Biol. Chem. 255, 6456-6461; Singh T J, Akatsuka A, Blake K R and Huang K P. (1983). Arch. Biochem. Biophys. 220, 615-622; Singh T J, Grunke-Iqbal I and Iqbal K. (1995). J. Neurochem. 64, 1420-1423; and transcriptional components such as RNA polymerases I and II, SV40 T antigen and CREM Dahmus ME. (1981). J. Biol. Chem. 256, 11239-11243; de Groot R P, den Hertog J, Vandenhee de J R, Grois J and Sassone-Corsi P. (1993). EMBO J, 12, 3903-3911; Grässer F A, Scheidtmann K H, Tuazon P T, Traugh J A and Walter G. (1988). Virology 165, 13-22).
CK1 isoforms can influence the development of tumors in many ways. Their ability to modulate p53 and Mdm2 functions through site-directed phosphorylation, their function in centrosome and spindle regulation, the opposite roles of CK1 isoforms in Wnt signaling and their involvement in impeding apoptosis demonstrate the potential role of CK1 family members in proliferative diseases on multiple levels. Different isoforms seem to play an important role in the development and progression of certain tumor types. Therefore, the interest in targeting CK1 for drug development has increased within the last 5 years. The role of the casein kinase 1 (CK1) family in different signaling pathways is linked to cancer development (Uwe Knippschild et. al., Onkologie 2005; 28:508-514). Further information on specific disorders connected with the casein kinase 1 (CK1) family has been published in: Uwe Knippschild et al., Cellular Signalling 17 (2005) 675-689.
The Wnt and Hedgehog pathways are involved in the regulation of stem cell identity and the initiation and maintenance of many tumor types. Dysregulation of these pathways play an important role in cancer stem cell maintainence. Casein kinases 1ε and 1δ are mainly positive modulators of the Wnt and the Hh pathways. Thus, selective inhibition of Casein kinases 1ε and 1δ inhibit the proliferation and self renewal of cancer stem cells.
Multiple members of the casein kinase I family of serine/threonine protein kinases can have positive or negative effects on individual regulatory elements of the Wnt and Hedgehog pathway, which in summary leads to inhibition. These roles, including recent results on Casein kinase 1 (CK1) phosphorylation and activation of LRP6, CKI phosphorylation of Ci and mediation of Ci-Slimb/β-TrCP binding were revived (“CKI, There's more than one: casein kinase I family members in Wnt and Hedgehog signaling” Price M A, Genes & Dev. 2006. 20: 399-410). Both the Wnt and Hh signaling pathways are important in many developmental patterning events.
Alzheimer's disease is an age-related disorder characterized in part by the appearance of intracellular lesions composed of filamentous aggregates of the microtubule-associated protein tau. Abnormal tau phosphorylation accompanies tau aggregation and is considered to be an upstream pathological event in this disease. Enzymes implicated in tau hyperphosphorylation in Alzheimer's disease include members of the casein kinase 1 family. (Kannanayakal, T J et al. Nuerosci Lett. 2008; 432(2): 141-5.)
The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder and metabolic disorders. Casein kinase 1 epsilon (CK1ε) and casein kinase 1 delta (CK1δ) are Ser-Thr protein kinases, which are closely related to each other and serve as key clock regulators. This was demonstrated by mutations in CK1δ and CK1ε that dramatically alter the circadian period. Therefore, inhibitors of CK1 have utility in treating circadian disorders. (Walten, K. M. et al. JPET 330:430-439, 2009.)
Several publications describe casein kinase inhibitors: Wager Travis et. al. Abstracts of Papers, 238th ACS National Meeting, Washington, D.C., United States, Aug. 16-20, 2009; Oumata Nassima et al. Journal of Medicinal Chemistry Volume 51 Issue 17 Pages 5229-5242 Journal 2008; Mashhoon N. et al. J Biol Chem 200; 275(26): 20052-60; Pfeifer C. et al. J Med Chem. 2009 Dec. 10; 52(23):7618-30.
In addition several patent applications regarding CK1δ and/or ε inhibitors were published: US 2010/0179154 A1; US 2004/0110808 A1; US 2008/0027124 A1; US 2009/0099237 A1.
Several patents and patent applications described certain specific acyl-amino-benzimidazoles with pharmacological activity: EP 1 388 341 A1 and US 2004/0110808 A1; U.S. Pat. No. 7,132,438 B2; WO 2007/064932 A2; DE 27 54 930 A1; US 2003/0144286.